Tachykinins, a family of small peptides that share a common C-terminal sequence, are widely distributed in smooth muscle, peripheral nerves, the spinal cord and the brain. The actions of the five tachykinins are mediated primarily, but not exclusively, through three subtypes of receptors belonging to the G-protein linked neurokinin receptor family -- neurokinin Type 1 (NK1), neurokinin Type 2 (NK2), and neurokinin Type 3 (Nk30. The actions of Substance P, neurokinin A (NKA), and neurokinin B (NKB) (the three most common tachykinins) have been linked most closely with NK1, NK2, and NK3 receptors, respectively. Substance P, the most abundant mammalian tachykinin isolated, displays highest affinity for NK1. Substance P is located in several regions of the brain, and studies using the Substance P antagonist, MK-869, have shown that it is likely to be important in the pathogenesis of depression. In addition, Substance P may be one of several neurotransmitters involved with circadian rhythms. L-759274 is a potent and highly selective non-peptide NK1 receptor antagonist with a long duration of action in preclinical models. It is 3000-fold selective for the human NK1 receptor versus the human NK3 receptor, and >20,000-fold selective versus the human NK2 and other G-protein coupled receptors and ion channels that have been tested. L-759274 acts as a competitive antagonist of Substance P from at human NK1 receptors as it has no effect on the rate of dissociation of Substance P from this receptor but reduces the apparent affinity of the receptor for [1251]-Substance P. Preclinical work suggests that NK1 antagonist have significant potential in the treatment of disorders linked to CNS dysfuntion. Studies in gerbils and ferrets (species with human-like NK1 receptor pharmacology) have demonstrated that L-759274 is brain penetrant. In gerbils, systemic administration of L-759274, but not nonbrain penetrant NK1 receptor antagonists, can block the vigorous, hindfoot tapping response to NK1 receptor agonists injected intracerebroventricularly. Studies in ferrets have shown that L-759274 produces an inhibition of cisplatin-induced emesis in a dose-dependent manner and it is known that CNS penetration is essential for such anti-emetic activity. Furthermore, L-759274 given at a dose of 1 mg/kg I.P. abolishes the emetic response evoked by centrally acting emetogens, such as morphine and apomorphine. There have been no signs of somnolence or sedation in any of the animal models. There are several observations which suggest that NK-1 antagonists might have potential efficacy in the treatment of sleep disorders: (1) improvement on the item of the Hamilton Depression Scale which quantifies "difficulty falling asleep" within the first week of 300 mg of MK-0869, a highly selective NK1 antagonist, (2) somnolence (as an adverse experience; incidence ~20%, twice that observed on placebo), which appeared after days to weeks of treatment with MK-0869 300 mg, (3) somnolence as the only prominent adverse experience in normal subjects dosed with L-759274 during the day, and (4) improved sleep quality and decreased sleep latency (quantitated through questionnaire) following evening doses of L-759274 in healthy elderly subjects. The exact mechanism by which a Substance P antagonist might improve sleep is not currently known. It is likely that sleep enhancing effects are generally NK1 antagonism based, as these effects (described above) were observed to varying extents with two distinct NK1 antagonists, MK-0869 and L-759274. However, L-759274 in healthy volunteers appears to be more sedative than MK-0869, and it is speculated that this might occur either because L-759274 enters brain much more rapidly than MK-0869, or because of an as yet uncharacterized mechanism. Preclinical data have shown that Substance P antagonists are able to cause phase shifts in locomotor activity in hamsters. However, a single dose clinical study of 300 mg MK-0869 in normal men did not demonstrate a significant effect of a Substance P antagonist on bright light-induced melatonin suppression (MRL Memo). Thus, the mechanism of the potential effect on sleep remains unknown at present.